When antibiotics are administered, either orally or parenterally, a significant fraction of the administered dose reaches the late ileum or colon in an active form and comes into close contact with the bacterial population that is present in the colon. The alarming consequences of this have been known for years and constitute the subject of a ECDC/EMEA Joint Technical Report called “The bacterial challenge: time to react, A call to narrow the gap between multidrug-resistant bacteria in the EU and the development of new antibacterial agents” published in September 2009. The residual antibiotic exerts a selective pressure on the bacteria present in the colon and provokes the emergence and development of bacteria resistant to the antibiotic. Because the genetic determinants of resistance to various antibiotics are often physically linked on mobile genetic elements such as plasmids and transposons, the treatment with a single antibiotic often selects for the simultaneous presence of several antibiotic resistance genes, thus explaining how multi-antibiotic resistance can emerge very fast.
As a result of this process, the patient or the animal that has received an antibiotic treatment becomes very rapidly and strongly colonized by antibiotic-resistant bacteria. This can result in complicated further infections by resistant bacteria as well as the dissemination of resistance to other bacteria, and ultimately the environment.
It is now widely accepted that the selection and dissemination of such resistant bacteria is a major factor that increases significantly the dissemination of bacterial resistance to antibiotics both in the community and in hospitals. Levels of bacterial resistance are currently extremely high and increasing year after year becoming a major public health problem worldwide that could lead to major outbreaks of infections very difficult to treat with available antibiotics either in humans or in animals.
Besides producing antibiotic-resistant bacteria, antibiotics that reach the colon in active form will also profoundly alter the composition of the commensal flora and eliminate susceptible bacterial species. Among those bacteria, susceptible anaerobic bacteria can be eliminated; they are known to play a major physiological role in the intestine of normal subjects and animals. For example, they act to prevent colonization by exogenous potentially pathogenic microorganisms such as Clostridium difficile and/or Candida sp, and/or multiresistant exogenous bacteria such as Vancomycin-resistant enterococci. It is therefore essential to prevent elimination of such useful bacteria to prevent adverse effects of antibiotics, which can lead to the appearance of pathologic signs and symptoms, such as post-antibiotic diarrhea or the more severe forms of pseudomembranous colitis, Candida genital infections, particularly in women, or antibiotic-resistant systemic infections in hospitalized patients, particularly those in intensive care.
One way to prevent such adverse effects of antibiotic treatments is to eliminate residual antibiotics that arrive in the caecum and colon; in the recent years, there have been two different approaches to achieve this goal. One has been the delivery to the gut of enzymes that specifically degrade antibiotics (such as those described in US20050249716). Alternatively, the formulation of an adsorbent for a site-specific intestinal delivery has been proposed in applications WO2006/122835 and WO2007/132022. The adsorbent would act by sequestering the antibiotic before it can affect susceptible bacteria in the caecum and colon. This approach would enable to broaden the spectra of antibiotics that may be eliminated as compared to previous approaches based on antibiotic-specific enzymes. Adsorbents, and in particular activated charcoal, are very challenging products to formulate because of their physicochemical properties such as low density, hydrophobicity, wetting properties, etc. Attempting to formulate activated charcoal for an intestinal site-specific delivery of an oral dose is not possible using conventional direct compression because of the very low cohesive properties of activated charcoal. Even simple wet granulation and compression lead to tablets exhibiting poor adsorption properties and poor disintegration profile. Enzyme-based delivery systems have been proposed to overcome these problems. These systems are based on their degradation and subsequent release of their content in the colon as a result of the action of colonic enzymes on a polymer encapsulating the adsorbent. A representative system implements pectin beads specifically degraded by pectinolytic enzymes which are produced in the colon of many mammals by bacteria of the commensal flora (such as those described in WO2006/122835). However, this system presents limitations such as low adsorbent content and difficulties in up scaling the production of pectin beads. Also, variability in the amount of pectinolytic enzymes present in the colon has led to variability in the delivery of the adsorbent. Solid dosage forms, either in single dosage form such as tablet or in a multi-dispersed pellet formulation, have also been proposed, with an excellent yield and adsorbent content (WO2007/132022). However, even though formulations could be made in a straightforward manner, their disintegration properties and the adsorption efficiency of the released adsorbent could be improved in a more satisfactory manner.
It would be advantageous to develop a formulation appropriate for the delayed release of an adsorbent in the later parts of the gastrointestinal tract yet preserving as much as possible the adsorption characteristics of the adsorbent. It would also be advantageous to produce a formulation with an improved adsorbent-release profile, with a release of the adsorbent at a place and time in the gastrointestinal tract where no more antibiotic is absorbed. This would prevent any interaction of the adsorbent with the normal absorption process of antibiotics, or any other pharmaceutical product, when given simultaneously by oral route.
Such formulation would be advantageous in removing residual antibiotics and/or their active metabolites from the intestinal tract while being able to be co-administered with large number of antibiotics and to reduce unwanted antibiotic-associated side-effects such as diarrhea, abdominal pain, and bacterial resistance to antibiotics. It would also be advantageous to have formulations that provide a specific release of an adsorbent in the lower part of the gastrointestinal tract, specifically in the late ileum, the caecum, or the colon.
Such formulation would also be advantageous in reducing or eliminating the side effects of pharmaceutical agents or metabolites thereof in the late ileum, caecum and colon. Such pharmaceutical agents are for example agents which are administered to treat a disease state, but which have side effects when they reach the lower part of the gastroinstestinal tract, specifically in the late ileum, the caecum, or the colon. Representative, non limiting, examples of such pharmaceutical agents include irinotecan and its metabolite SN-38, diacerhein, Pancrelipase (such as Pancrease, Creon, Zenpep), Phosphodiesterase 4 inhibitors used in the treatment of chronic obstructive pulmonary disease such as Roflumilast or Cilomilast, or anti-mitotic and anti-inflammatory drugs such as colchicine.
Furthermore, such formulation would be advantageous in the treatment of disease states characterized by the accumulation of substances in the lower part of the gastroinstestinal tract, this accumulation being responsible for the development of a number of pathological conditions. For example, the formulation can be useful for the treatment of conditions such as, but not limited to, hepatic encephalopathy, irritable bowel syndrome, chronic renal disease, C. difficile associated diarrhea or antibiotic associated diarrhea. Representative substances which can be adsorbed by the formulation disclosed herein include, but are not limited to, ammonia, indoles, advanced glycation end products (AGEs) and certain bacterial toxins.
More generally, the formulation of the invention can be used in the treatment of a condition, either pathological or not, which is caused, maintained and/or enhanced by the presence, or the presence in excess quantities, of certain substances in the lower part of the gastrointestinal tract, specifically in the late ileum, the caecum, or the colon.
The present invention provides such formulations and methods of preparation and use thereof.